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Role of estrogen receptors in pancreatic beta-cell survival and insulin secretion

雌激素受体在胰腺β细胞存活和胰岛素分泌中的作用

基本信息

批准号：
7787369
负责人：
Franck Mauvais-Jarvis
金额：
$ 4.89万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-15 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7787369
关键词：
Apoptosis Biology Cell Death Cell Survival Cells Cessation of life Data Dependence Development Diabetes Mellitus Estradiol Estrogen Receptors Estrogens Event Female Gender Genetic Goals Gonadal Steroid Hormones Health Human In Vitro Incidence Individual Insulin Investigation Knockout Mice Knowledge Membrane Mission Mitochondria Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Pancreas Pathway interactions Physiological Physiological Processes Physiology Play Principal Investigator Production Protocols documentation Qualifying Research Research Personnel Research Proposals Role Staging Streptozocin Structure of beta Cell of islet Testing Therapeutic Therapeutic Intervention United States National Institutes of Health base cell injury cytokine diabetic diabetic patient experience improved in vivo innovation insulin secretion islet novel oxidative damage prevent programs receptor tool

项目摘要

In diabetes, the death of insulin-producing ß-cells in the pancreas by apoptosis leads to insulin dependence. Yet, the events that promote ß-cell death are still not fully understood. It is essential to increase our basic knowledge of the processes regulating beta-cell survival in order to develop novel and efficient therapies for diabetic patients. Evidence suggests that the female hormone, 17 ß-estradiol (estradiol), protects insulin production and prevents diabetes. Although estradiol acts primarily via two distinct estrogen receptors (ERs), ERalpha and ERbeta, recently, the G protein-coupled estrogen receptor (GPER), also called GPR30 has been recognized as a putative membrane receptor for estrogens that mediates a series of non-genomic E2 signals. The individual contributions of these ERs in protecting ß-cell survival have not been established. Our objective for this exploratory application is to elucidate the contribution played by non-classical estrogen actions via GPER in ß-cell survival in vivo, through the use of genetic mouse models. We will use a combined ß-cell specific ERalpha/ERbeta deficient mouse (ßERabKO) and a GPER deficient mouse. Using these tools, in combination with pharmacological probes, we will study the role of GPER actions in beta-cell survival in vivo and in cultured islet. Through the proposed research - which is the first investigation of rapid, non genomic ERs in ß-cell survival in vivo - we plan to demonstrate that GPER is important to ß-cell survival in vivo, and therefore represent a viable targets for therapeutic intervention.

在糖尿病中，胰腺中产生胰岛素的胰岛β细胞因凋亡而死亡，导致胰岛素依赖。然而，促进β-细胞死亡的机制仍然没有完全弄清楚。为了开发新的有效的糖尿病治疗方法，增加我们对β细胞存活调节过程的基础知识是至关重要的。患者有证据表明，女性激素，17 β-雌二醇（雌二醇），保护胰岛素的生产和预防糖尿病。虽然雌二醇主要通过两种不同的雌激素受体起作用， (ERs)最近，G蛋白偶联雌激素受体（GPER），也被称为GPR 30，已被认为是雌激素的假定膜受体，其介导一系列的雌激素受体调节。非基因组E2信号。这些ER在保护胰岛细胞存活方面的单独贡献尚未确定。我们的目的是为这个探索性的应用程序是阐明的贡献，通过使用遗传小鼠模型，通过GPER在体内β细胞存活中的非经典雌激素作用。我们将使用联合的β细胞特异性ER α/ER β缺陷小鼠（β ERabKO）和GPER缺陷小鼠.使用这些工具，结合药理学探针，我们将研究GPER作用在体内和培养的胰岛β细胞存活中的作用。通过拟议的研究-这是第一次调查快速，非基因组ER在体内的肿瘤细胞存活-我们计划证明GPER是重要的肿瘤细胞存活在体内，因此代表了一个可行的治疗干预的目标。